The Epidemiology Branch (DESPR) is conducting a number of studies in collaboration with the Health Research Board and Trinity College, Ireland. These investigations are designed to determine the biochemical mechanisms by which folate reduces the risk for neural tube defects. Data and blood samples have been collected on a large proportion of Irish women delivering babies in Dublin. Samples from women whose pregnancy ended in the delivery of a child with a neural tube defect and control women whose pregnancy ended in the delivery of a normal child are being studied. Samples are also being collected from families with an affected child. Various aspects of folate metabolism and other nutritional measures are being examined. We have demonstrated that at lower levels of B12, women carrying a fetus with an NTD have significantly higher levels of homocysteine than women carrying a normal fetus. We have also demonstrated that an abnormal gene responsible for elimination of homocysteine is involved. Specifically, a gene defect produces the so-called thermolabile variant of the 5,10 methylene tetrahydrofolate reductase enzyme. This abnormal enzyme is found significantly more frequently in individuals with NTDs than in normal individuals. We have recently published a report showing that the presence of the thermolabile variant of MTHFR is associated with significantly reduced levels of red cell folate. A paper in press shows that the enzyme responsible for most cases of homocystinuria, cystathionine synthase, is not an important cause of neural tube defects despite its association with high homocysteine.